Formulation of a fibrin sealant mimics the last step of the coagulation cascade wherein the enzyme thrombin cleaves fibrinogen which is then cross-linked into a semi-rigid or flexible fibrin clot. This fibrin clot adheres to wound sites, forming a barrier to fluid leaks and generates adhesion between tissues, while providing hemostatic and healing properties to the treated site.
Presently marketed, applicant's CryoSeal™ system is a device which harvests cryoprecipitated, concentrated clotting and adhesive proteins, including fibrinogen and Factor XIII from a donor's plasma in approximately one hour. The one hour cryoprecipitation harvesting, provided by the CryoSeal™ system, compared to the 1 to 2 day cryoprecipitation process routinely practiced in Blood Banks, means that CryoSeal™ harvesting of clotting and adhesive proteins can occur right in the perioperative theater with the patient close by, thereby avoiding the need to initiate the process days in advance.
These CryoSeal™ harvested clotting and adhesive proteins, when combined with bovine or human thrombin, forms a biological glue useful for surgical hemostasis and tissue adhesion. Commercially available thrombin, however, is generally sourced from bovine or human plasma pools, so the patient would still be at risk of negative immune reactions or contamination by infectious blood born viruses and, possibly Crutzfeld-Jacobs Disease (CJD) or new variants of CJD (NVCJD). An advantage of the CryoSeal™ cryoprecipitation invention is that the harvested clotting and adhesive proteins sourced from the patient's own blood eliminates the risk of contamination by infectious blood-born disease when these clotting and adhesive proteins are topically applied to the patient's surgical wound sites.
It has long been understood, however, that the safest condition for a surgical patient would result from a two component biological sealant preparation in which the thrombin component would be harvested from the same donor in which the clotting and adhesive protein component was harvested—forming a fully autologous biological sealant or glue.
For instance, Cederholm-Williams PCT Patent (WO94/00566-6 Jan. 1994) clearly describes an improved fibrin glue in which the thrombin component whose preparation method,—adjusting the ionic strength of the blood and pH of the plasma to cause precipitation of a thrombin component for later resolubalization—was described therein, would be combined with a fibrinogen component also sourced from the plasma of the same donor. These steps are so time consuming they become impractical for use in the perioperative theater where processing times should be less than one hour.
Three years later, in 1997, Hirsh, et al. (U.S. Pat. No. 5,643,192) follows the lead of Cederholm-Williams by also teaching a method of preparing fibrin glue in which both the fibrinogen and thrombin components of a fibrin glue are sourced from the same donor's plasma. The Hirsh patent describes a method of preparing thrombin in which the fibrinogen in the plasma is first precipitated to prepare a supernatant and then clotting the residual fibrinogen in the supernatant which is different than the method taught by Cederholm-Williams, but does not result in a commercially useful thrombin in that (see FIG. 1 of Hirsh, et al.) the thrombin provides clotting times of five seconds or less for only 4 minutes, and less than 10 seconds for only 47 minutes.
These clotting times are unsuitable to the needs of surgeons who could not plan their entire surgeries around the limitations of the Hirsh, et al. fibrin glue.
These clotting speeds are unsuitable to the needs of surgeons who could not plan their entire surgeries around the limitations of the Hirsh, et al. fibrin glue.
Surgeons predominately require a fast acting clotting time (<5 seconds) for hemostasis and tissue sealing or adhesion. Slow clotting biological glues (>5 seconds) will often be transported away from the wound site by oozing and bleeding before they can perform their function. A surgeon utilizing the Hirsh fibrin glue would be required to arrange his surgery so that the hemostasis and tissue sealing intended for treatment with the Hirsh fibrin glue would occur within the 4 minute window where the clotting time was less than 5 seconds, making the Hirsh invention totally impractical for most surgeries which predominantly require rapid hemostasis and tissue adhesion throughout the surgery, the time span of which could extend to six hours.
The following prior art reflects the state of the art of which applicant is aware and is included herewith to discharge applicant's acknowledged duty to disclose relevant prior art. It is stipulated, however, that none of these references teach singly nor render obvious when considered in any conceivable combination the nexus of the instant invention as disclosed in greater detail hereinafter and as particularly claimed.
PATENT NO.ISSUE DATEINVENTORU.S. PATENT DOCUMENTS5,648,265Jul. 15, 1997Epstein5,510,102Apr. 4, 1996Cochrum5,585,007Dec. 17, 1996Antanavich, et al.5,605,887Feb. 25, 1997Pines, et al.5,614,204Mar. 25, 1997Cochrum5,631,019May 20, 1997Marx5,643,192Jul. 1, 1997Hirsh, et al.FOREIGN PATENT DOCUMENTSWO 94/00566Jan. 6, 1994Cederholm-Williams, et al.EU 0 592 242 A1Apr. 13, 1994E. R. Squibb & Sons
The other prior art listed above, not all of which are specifically discussed catalog the prior art of which the applicant is aware. These undiscussed references diverge even more starkly from the instant invention specifically distinguished below.